Role of melatonin in carcinogenesis and metastasis: From mechanistic insights to intermeshed networks of noncoding RNAs.

In recent years, seminal studies have been devoted to unraveling the puzzling mysteries associated with the cancer preventive/inhibitory role of melatonin. Our current knowledge of the translational mechanisms and the detailed structural insights have highlighted the characteristically exclusive role of melatonin in the inhibition of carcinogenesis and metastatic dissemination. This mini-review outlines recent discoveries related to mechanistic role of melatonin in prevention of carcinogenesis and metastasis. Moreover, another exciting facet of this mini-review is related to phenomenal breakthroughs linked with regulation of noncoding RNAs by melatonin in wide variety of cancers.

Mechanistic role of pyroptosis in tumor microenvironment and tumor immunotherapy.

In recent decades, extraordinary attention has been devoted to cell death pathways principally because of multifaceted regulatory roles in normal developmental and pathophysiological processes. The removal of functionally defective, infected or potentially malignant cells is regulated by programmed cell death (PCD) cascades.  Pyroptotic cell death is a highly complicated pro-inflammatory form of cell death. Pyroptosis is characterized by the formation of pores in the plasma membrane by oligomerization of the N-terminal fragment of gasdermins (gasdermin-NT) following the cleavage of gasdermin. Pyroptosis plays a pivotal role in the innate immune responses and mechanistically steered by inflammasome-mediated and inflammasome-independent cascades. In this review, we have comprehensively analyzed how different signaling pathways regulated pyroptosis in cancer inhibition and metastatic spread of cancer cells to the secondary sites. Comprehensive understanding of the interconnection between signaling pathways and pyroptosis will enable us to reap maximum benefits from the exciting mechanistic insights gained from pioneering studies related to pyroptosis.

The effect of Cornus mas extract on nicotine-induced oxidative stress and intratesticular damage in male rats.

The role of oxidative stress in disease pathogenesis has been extensively investigated. Researchers have gathered sufficient evidence related to oxidative stress-mediated intratesticular damage. The aim of this was study to evaluate the effects of Cornus Mas (CM) extract on intratesticular changes in rats exposed to nicotine. Thirty Wistar albino rats were divided into four groups. The groups and the administrated agents for 35 days were as follows; Control group (n=6): 0.9% saline, intraperitoneally; Nicotine group (n=7): 4 mg/kg nicotine, subcutaneous; CM group (n=7): 1000 mg/kg CM extract in 0.5 ml saline, via gavage; Nicotine + CM Group (n=8): 4 mg/kg Nicotine, subcutaneous + 1000 mg/kg CM extract via gavage. One rat each from the groups Nicotine and CM died.  In spermatogenetic and histopathological examination, significant positive changes were detected in nicotine + CM group regarding seminal parameters, apoptotic cells, Factor VIII and Johnsen score as compared to nicotine group. Oxidative stress markers were higher in nicotine group as compared to the control group. OSI and MDA levels were found to be reduced in nicotine + CM group than nicotine group. Nicotine induced a significant increase in TNF-α and IL-6 levels compared to the control group; however, CM effectively counteracted this increase. We have shown that nicotine increases testicular damage, causes apoptosis of testicular cells and adversely affects spermatogenesis by increasing inflammation. We concluded that CM extract exerted beneficial effects on spermatogenesis and minimized testicular parenchymal damage, apoptosis and angiogenesis. Rapidly increasing understanding of the complexity of oxidative stress in intratesticular is the key to unlocking the potential of ROS-targeting therapies.

Mutation analysis of the TERT gene in ovarian cancer patients of the Turkish population by next generation sequencing method.

Ovarian cancer (OC) ranks seventh among malignant tumors worldwide. As one of the most common gynecological malignancies, ovarian cancer has the second-highest mortality rate, after cervical and uterine cancer. Next-Generation Sequencing (NGS) technology has enhanced multi-gene panel analysis and its clinical utility for identifying cancer-causing gene mutations. This study aimed to determine the presence of significant and nonsense mutations in telomerase reverse transcriptase (TERT), alpha-thalassemia/mental retardation, X-linked (ATRX), O-6-methylguanine-DNA methyltransferase (MGMT), and isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes using the Next-Generation Sequencing (NGS) method. A cohort of 33 patients diagnosed with ovarian cancer was included in this investigation, and peripheral blood samples were collected from all participants. Significant and nonsense mutations in TERT, ATRX, MGMT, IDH1, and IDH2 genes were detected using the Next-Generation Sequencing method. Bioinformatics analysis was conducted using the QIAGEN Clinical Insight system. Twenty-four patients exhibited seven different TERT mutations, occurring in both exonic and intronic regions. One patient displayed a c.699-3delC deletion in the intronic region of the IDH1 gene, and the c.532G > A (p.V178I) mutation observed in three patients was assessed as potentially harmful. Additionally, novel mutations c.881A > G and c.995A > G were observed in the ATRX gene. The heterozygous novel mutation identified in the ATRX gene was confirmed through Sanger sequencing. These mutations were not previously associated with ovarian cancer and are considered novel candidate markers for ovarian cancer susceptibility. Confirmation of these results through larger cohort studies or functional investigations will contribute to a better understanding of the molecular mechanisms underlying ovarian cancer.

Regulatory role of circular RNAs in oral squamous cell carcinoma.

OSCC is a genomically complicated disease and advancements in the modern era of molecular oncology have enabled researchers to portray near-to-complete resolution of signaling landscape. Over the last two decades, overwhelming proof-of-concept has established mechanistic regulatory role of non-coding RNAs in carcinogenesis, including OSCC. Circular RNAs demonstrate a burgeoning facet of oncology research and molecular biologists are only beginning to appreciate and recognize the significance of circRNAs in the pathogenesis of OSCC. Regulatory roles of non-coding RNAs in the re-shaping of signaling pathways offer plausible strategies for prevention/inhibition of OSCC. Circular RNAs have mechanistic roles in OSCC and "sponge effects" mediated by a wider variety of circRNAs need to be rationally targeted for effective cancer prevention. Phenomenal and cutting-edge research works in different types of animal models will further refine our knowledge for selection of most promising circRNAs as pharmacologically valuable targets.

Polyphenol-Based Nanoparticles: A Promising Frontier for Enhanced Colorectal Cancer Treatment.

Colorectal cancer (CRC) poses a significant challenge in healthcare, necessitating the exploration of novel therapeutic strategies. Natural compounds such as polyphenols with inherent anticancer properties have gained attention as potential therapeutic agents. This review highlights the need for novel therapeutic approaches in CRC, followed by a discussion on the synthesis of polyphenols-based nanoparticles. Various synthesis techniques, including dynamic covalent bonding, non-covalent bonding, polymerization, chemical conjugation, reduction, and metal-polyphenol networks, are explored. The mechanisms of action of these nanoparticles, encompassing passive and active targeting mechanisms, are also discussed. The review further examines the intrinsic anticancer activity of polyphenols and their enhancement through nano-based delivery systems. This section explores the natural anticancer properties of polyphenols and investigates different nano-based delivery systems, such as micelles, nanogels, liposomes, nanoemulsions, gold nanoparticles, mesoporous silica nanoparticles, and metal-organic frameworks. The review concludes by emphasizing the potential of nanoparticle-based strategies utilizing polyphenols for CRC treatment and highlights the need for future research to optimize their efficacy and safety. Overall, this review provides valuable insights into the synthesis, mechanisms of action, intrinsic anticancer activity, and enhancement of polyphenols-based nanoparticles for CRC treatment.

The serum steroid signature of PCOS hints at the involvement of novel pathways for excess androgen biosynthesis.

CONTEXT: Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of androgen excess is hirsutism, while the best biochemical parameter is still a matter of debate. Current consensus guidelines recommend, among other hormones, serum free testosterone as an important serum parameter to measure androgen excess. Recently, however, novel active androgens and androgen metabolic pathways have been discovered. OBJECTIVE: To assess the contribution of novel androgens and related steroid biosynthetic pathways to the serum steroid pool in PCOS women in comparison to healthy controls. DESIGN: This is a case control study, wherein PCOS was diagnosed according to the AE-PCOS 2009 criteria. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. SETTING: Yeditepe University and associated clinics in Istanbul, Turkey, together with Bern University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS: 42 PCOS women and 42 matched, healthy control women. MAIN OUTCOME MEASURES: Assessment of 34 steroids compartmentalized in four androgen related pathways: the classic androgen pathway, the backdoor pathway, the C11-oxy backdoor pathway, and the C11-oxy (11ß-hydroxyandrostenedione) pathway. RESULTS: Metabolites of all four pathways were identified in healthy and PCOS women. Highest concentrations were found for progesterone in controls and androstenedione in PCOS. Lowest levels were found for 11-ketotestosterone in controls compared to PCOS, and for 20α-hydroxyprogesterone in PCOS compared to controls. PCOS also had higher serum testosterone levels compared to the controls. PCOS women had overall higher levels of steroid metabolites of all four androgen pathways compared to healthy controls. CONCLUSIONS: Novel alternative pathways contribute to the androgen production in healthy and PCOS women. Hyperandrogenism in PCOS is characterized by an overall increase of serum androgens in the classic, backdoor and C11-oxy pathways. While monogenetic disorders of steroid biosynthesis can be recognized by a specific pattern in the steroid profile, no diagnostic pattern or classifier was found in the serum for PCOS.

Evaluation of the protective role of resveratrol against sepsis caused by LPS via TLR4/NF-κB/TNF-α signaling pathways: Experimental study.

The development and progression of sepsis are multifactorial and influence the immunological, endocrine, and cardiovascular systems of the body. Our knowledge of the key mechanisms involved in the pathogenesis of sepsis has expanded exponentially, yet this still needs to be translated into effective targeted therapeutic regimes. In the present study, we aimed to determine whether resveratrol has positive effects in the experimental sepsis rat model. Twenty-eight male Spraque-Dawley rats were randomly divided into four groups (n = 7) as follows: control, lipopolysaccharide (LPS) (30 mg/kg dose), resveratrol, and LPS and resveratrol. After the experiment, liver and kidney tissues were collected for histopathological evaluation, blood serums were collected to measure malondialdehyde levels with enyzme-linked immunosorbent assay, and Toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) immunoreactivity density was evaluated immunohistochemically. In addition, messenger RNA expression levels for TLR4, TNF-α, NF-κB, interleukin-1ß, and interleukin 6 were measured. In addition, the damage observed in liver and kidney tissue was determined by AgNOR (argyrophilic nucleolar organizer regions) staining. LPS application caused severe tissue damage, oxidative stress, and increased the expressions of proinflammatory proteins and genes we evaluated, while resveratrol application eliminated these negativities. Resveratrol has been proven to suppress the TLR4/NF-κB/TNF-α pathway, a possible therapeutic signaling pathway that is important in initiating the inflammatory response in an animal model of sepsis.

Role of Platelet-Derived Growth Factor-mediated signaling in carcinogenesis and metastasis.

Platelet-Derived Growth Factor (PDGF) mediated signaling has emerged as one of the most extensively studied cascades in cancer development and progression. Overwhelmingly increasing data obtained from preclinical and clinical studies has helped us to develop a near-complete resolution of PDGF/PDGFR signaling landscape. Phenotype- and genotype-driven studies have provided proof-of-concept that therapeutic targeting of PDGF/PDGFR signaling axis is necessary to improve clinical outcome.   Kinase inhibitor drug discovery programmes have broadened their focus to include a wide variety of kinase targets. Based on the insights gleaned from previously published high-impact research, it is clear that different transduction cascades crosstalk with PDGF/PDGFR signaling during primary tumor invasion, dissemination and ultimate metastasis of cancer cells. In this commentary, we will focus on involvement of PDGF/PDGFR signaling in different cancers and how pharmacological targeting of this signaling cascade inhibits cancer progression.

Silymarin protects the liver from α-naphthylisothiocyanate-induced cholestasis by modulating the expression of genes involved in bile acid homeostasis.

Cholestasis is characterized by impaired bile flow which results in inflammation, cirrhosis, and ultimately liver failure. The current study is aimed to evaluate the anti-cholestatic effect of silymarin against α-naphthylisothiocyanate (ANIT) induced cholestasis. Mice were gavaged with various doses of silymarin or ursodeoxycholic acid (UDCA) for 19 days. Then they were challenged with α-naphthylisothiocyanate (ANIT) and after 48 hours the animals were sacrificed to obtain blood and liver sections. Serum levels of bilirubin, aspartate transaminase (AST), alanine transaminase (ALP), and liver histology were analyzed. mRNA expression of selected transporters (Bile salt export pump (BSEP) and sodium taurocholate cotransporting polypeptide (NTCP)) and proteins (farnesoid x receptor (FXR) and Cytochrome P450 Family 7 Subfamily A Member 1 (Cyp7a1)) involved in bile acids biosynthesis, excretion and uptake were also evaluated by quantitative PCR. The results indicated that the serum levels of bilirubin, AST, and ALP were significantly higher in a cholestatic model group as compared to an untreated control group. However, in silymarin groups, the serum level of these parameters is significantly lower than in a cholestatic model group. Liver histology also showed that silymarin prevents ANIT-induced hepatic injury. mRNA expression of FXR, BSEP, and NTCP was downregulated and expression of Cyp7a1 was upregulated in a cholestatic model group as compared to an untreated control group. However, in silymarin treatment groups, the expression of FXR, BSEP and NTCP was upregulated and the expression of Cyp7a1 was downregulated as compared to the cholestatic model group. In conclusion, silymarin could alleviate hepatic injury by modulating the expression of genes involved in bile acid homeostasis.

Multifunctional role of Nobiletin in cancer chemoprevention.

The diversity of highly bioactive and pharmacologically active natural products which recognize essential biological targets having exquisite specificity, constitutes a massive pharmacological database for discovery of valuable drugs. The rapid accumulation of information has revealed chemopreventive role of nobiletin against wide variety of cancers. Recent efforts are now being expanded and new integrative omics technologies have illuminated continuously upgrading list of molecular mechanisms which underlie carcinogenesis and metastasis. In this mini-review, we explore the progress that has been made in the identification of promising molecular targets of nobiletin.

Frontiers of Ferroptosis in Cancer Treatment.

Recent phenomenal advancements in genomic and proteomic technologies and rapid breakthroughs in the interpretation of large gene expression datasets have enabled scientists to comprehensively characterize the gene signatures involved in ferroptosis. Ferroptosis is an iron-dependent form of non-apoptotic cell death that has gained the worthwhile attention of both basic and clinical researchers. Ferroptosis has dichotomous, context-dependent functions both as a tumor suppressor and promoter of carcinogenesis. Essentially, pharmacological modulation of ferroptosis by its induction as well as its inhibition holds enormous potential to overcome drug resistance and to improve the therapeutic potential of chemotherapeutic drugs in a wide variety of cancers.

Regulation of Cell Signaling Pathways by Genistein in Different Cancers: Progress, Prospects and Pitfalls.

On the translational front, integrative genomic approaches have spurred the identification of diverse mechanisms of drug resistance, tumor heterogeneity, metastasis and emerging preclinical targets. Recent breakthroughs in oncogenic cell signaling pathways have forged new links and multi-disciplinary researchers have unraveled different facets of signaling landscapes. Natural product research has witnessed breakneck developments mainly in the context of the ever-expanding list of bioactive components having significantly pharmacological properties. Genistein has gradually gained appreciation because of its multifaceted roles in the prevention and inhibition of carcinogenesis and metastasis. More importantly, the entry of genistein into various phases of clinical trials substantiates the medicinal and pharmacological significance of genistein in cancer chemoprevention. In this review, we have attempted to summarize how genistein regulated different oncogenic pathways in carcinogenesis and metastasis. Furthermore, genistein-mediated regulation of non-coding RNAs is also an interesting feature that has been included in this review to realistically analyze how genistein-mediated control of miRNAs, lncRNAs and circRNAs influence carcinogenesis. In the later sections, we have provided a summary of clinical trials related to genistein for cancer prevention/inhibition. However, apart from the optimistic approaches to further investigate genistein-mediated cancer-inhibitory effects, certain hints have emerged which underscore the pro-metastatic role of genistein. Therefore, the pro-metastatic role of genistein in different cancers should be rationally tested in a broader context because these properties in the future may reduce the enthusiasm in the quest to pursue genistein as a potent cancer chemopreventive agent.

Anticancer and Anti-Metastatic Role of Thymoquinone: Regulation of Oncogenic Signaling Cascades by Thymoquinone.

Cancer is a life-threatening and multifaceted disease. Pioneering research works in the past three decades have mechanistically disentangled intertwined signaling networks which play contributory roles in carcinogenesis and metastasis. Phenomenal strides have been made in leveraging our scientific knowledge altogether to a new level of maturity. Rapidly accumulating wealth of information has underlined a myriad of transduction cascades which can be pharmaceutically exploited for cancer prevention/inhibition. Natural products serve as a treasure trove and compel interdisciplinary researchers to study the cancer chemopreventive roles of wide-ranging natural products in cell culture and preclinical studies. Experimental research related to thymoquinone has gradually gained momentum because of the extra-ordinary cancer chemopreventive multifunctionalities of thymoquinone. In this mini-review, we provide an overview of different cell signaling cascades reported to be regulated by thymoquinone for cancer chemoprevention. Essentially, thymoquinone efficacy has also been notably studied in animal models, which advocates for a rationale-based transition of thymoquinone from the pre-clinical pipeline to clinical trials.

The role of circulating miRNAs in leptin resistance in obese children.

OBJECTIVES: Leptin resistance is one of the important causes of obesity in children. Besides known causes of leptin resistance like mutations in leptin and leptin receptor genes, overexpression of SOCS3 in arcuate nucleus is a potential cause of leptin resistance. We aimed to determine the effects of circulating miRNAs on leptin resistance in obese children by targeting SOCS3 pathway. METHODS: miRNAs potentially targeting SOCS3 were determined by using online target prediction databases. Polymorphisms in miRNA target sequences were determined by using online genome browsers. miRNA expression levels of obese (n=35) and non-obese (n=30) children were determined by qPCR method, genotyping were performed by real-time PCR method and serum leptin, leptin receptor and SOCS3 levels were measured by ELISA method. RESULTS: miRNA profiling have shown that serum miR-218-5p levels are significantly (p<0.05) increased in accordance with serum leptin levels in obese children. CONCLUSIONS: In this study we used target prediction methods for evaluating potential miRNAs which may involve in development of leptin resistance. We have shown that miR-218-5p might be taking part in leptin resistance in obese children.

Regulation of ROCK1/2 by long non-coding RNAs and circular RNAs in different cancer types.

Recent breakthroughs in high-throughput technologies have enabled the development of a better understanding of the functionalities of rho-associated protein kinases (ROCKs) under various physiological and pathological conditions. Since their discovery in the late 1990s, ROCKs have attracted the attention of interdisciplinary researchers due to their ability to pleiotropically modulate a myriad of cellular mechanisms. A rapidly growing number of published studies have started to shed light on the mechanisms underlying the regulation of ROCK1 and ROCK2 via long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in different types of cancer. Detailed analyses have suggested that lncRNAs may be characteristically divided into oncogenic and tumor suppressor lncRNAs. Several exciting recent discoveries have also indicated how different lncRNAs and circRNAs modulate ROCK1/2 and mediate multistep cancer onset and progression. The present review chronicles the major advances that have been made in our understanding of the regulatory role of ROCK1/2 in different types of cancer, and how wide-ranging lncRNAs and circRNAs potentiate ROCK-driven signaling by blocking the targeting activities of tumor suppressor microRNAs.

Regulation of Cell-Signaling Pathways by Berbamine in Different Cancers.

Natural product research is a cornerstone of the architectural framework of clinical medicine. Berbamine is a natural, potent, pharmacologically active biomolecule isolated from Berberis amurensis. Berbamine has been shown to modulate different oncogenic cell-signaling pathways in different cancers. In this review, we comprehensively analyze how berbamine modulates deregulated pathways (JAK/STAT, CAMKII/c-Myc) in various cancers. We systematically analyze how berbamine induces activation of the TGF/SMAD pathway for the effective inhibition of cancer progression. We also summarize different nanotechnological strategies currently being used for proficient delivery of berbamine to the target sites. Berbamine has also been reported to demonstrate potent anti-cancer and anti-metastatic effects in tumor-bearing mice. The regulation of non-coding RNAs by berbamine is insufficiently studied, and future studies must converge on the identification of target non-coding RNAs. A better understanding of the regulatory role of berbamine in the modulation of non-coding RNAs and cell-signaling pathways will be advantageous in the effective translation of laboratory findings to clinically effective therapeutics.

Regulation of cell signaling pathways by circular RNAs and microRNAs in different cancers: Spotlight on Wnt/ß-catenin, JAK/STAT, TGF/SMAD, SHH/GLI, NOTCH and Hippo pathways.

Groundbreaking discoveries in molecular oncology have leveraged our understanding altogether to a new level. Mapping of plethora of cell signaling pathways has enabled researchers to drill down deep into the intermeshed regulatory networks which crosstalk to promote carcinogenesis and metastasis. More importantly, discovery of non-coding RNAs has added new layers of complexity to already complicated nature of cell signaling pathways. The discovery of circular RNAs (circRNAs) has opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by circRNAs. In this review, we have summarized most recent advancements in our understanding related to interplay between circular RNAs and microRNAs for the regulation of NOTCH, Wnt/ß-catenin, Hippo, SHH/GLI, JAK/STAT and TGF/SMAD pathways in different cancers.

Interaction of long non-coding RNAs and circular RNAs with microRNAs for the regulation of immunological responses in human cancers.

Advancements in single-cell RNA sequencing technologies have enabled us to deconvolve immune system heterogeneity by identification of functionally distinct immune cell subsets in disease and health. Discovery of non-coding RNAs has opened new horizons for re-interpretation of regulatory roles of myriad of cell signaling pathways in immunology and oncology. Role of miRNAs, circular RNAs and long non-coding RNAs (lncRNAs) in the context of immunomodulation has just begun to be uncovered and future studies may further expand the repertoire of non-coding RNAs implicated in the regulatory circuits. One of the most recent and exciting aspect in molecular immunology is the delivery of non-coding RNAs through exosomes to the recipient cells which results in the re-wiring of different pathways and protein networks in recipient cells. Broader understanding of all of the layers of regulation in this system can provide useful information that could be harnessed to rationally translate laboratory findings into clinically effective therapeutics.

Overview of the signaling pathways involved in metastasis: An intriguing story-tale of the metastatic journey of ovarian cancer cells.

Wealth of information has revolutionized our understanding related to the genetics and functional genomics of this heterogeneous disease. Keeping in view the heterogeneity of ovarian cancer, long-term survival might be achieved by translation of recently emerging mechanistic insights at the cellular and molecular levels to personalize individual strategies for treatment and to identify biomarkers for early detection. Importantly, the motility and invasive properties of ovarian cancer cells are driven by a repertoire of signaling cascades, many components of which have been experimentally verified as therapeutic targets in preclinical models as well as in clinical trials. Scientific evidence garnered over decades of research has deconvoluted the highly intricate intertwined network of intracellular signaling pathways which played fundamental role in carcinogenesis and metastasis. In this review we have provided a compendium of myriad of signaling cascades which have been documented to play critical role in the progression and metastasis of ovarian cancer. We have partitioned this multi-component review into different sections to individually discuss and summarize the roles of TGF/SMAD, JAK/STAT, Wnt/ß-Catenin, NOTCH, SHH/GLI, mTORC1/mTORC2, VEGFR and Hippo/YAP pathways in ovarian cancer metastasis.